Ethoxyquin is a Competent Radical-Trapping Antioxidant for Preventing Ferroptosis in Doxorubicin Cardiotoxicity
Ethoxyquin is a Competent Radical-Trapping Antioxidant for Preventing Ferroptosis in Doxorubicin Cardiotoxicity
复制标题
DOI：
10.1097/fjc.0000000000001328
复制
发表时间：
2022-07
影响因子：
3
通讯作者：
T. Tadokoro;Masataka Ikeda;K. Abe;T. Ide;H. Miyamoto;Shun Furusawa;Kosei Ishimaru;Masatsugu Watanabe;Akihito Ishikita;Shouji Matsushima;T. Koumura;Ken‐ichi Yamada;H. Imai;H. Tsutsui
中科院分区：
文献类型：
--
作者：
T. Tadokoro;Masataka Ikeda;K. Abe;T. Ide;H. Miyamoto;Shun Furusawa;Kosei Ishimaru;Masatsugu Watanabe;Akihito Ishikita;Shouji Matsushima;T. Koumura;Ken‐ichi Yamada;H. Imai;H. Tsutsui
阿霉素（DOX）是一种治疗多种恶性肿瘤的有效药物。然而，它有心脏毒性的副作用，称为阿霉素诱导的心肌病（DIC），这与预后较差有关。这种心脏毒性限制了DOX作为恶性肿瘤治疗剂的临床应用。近年来，铁凋亡（ferroptosis）被认为是DIC的主要病理生理机制之一。乙氧基喹啉是一种亲脂性抗氧化剂，广泛用于食品防腐，因此可能是一种潜在的预防DIC的治疗药物。然而，乙氧喹对铁凋亡和DIC的疗效仍有待充分阐明。在这里，我们研究了乙氧喹对GPx4缺陷型铁凋亡的抑制作用及其对培养的心肌细胞中的DOX诱导的细胞死亡和DIC小鼠模型中的心脏毒性的治疗效果。在培养的心肌细胞中，乙氧喹处理有效地防止GPx4缺陷型铁凋亡。乙氧喹也防止DOX诱导的细胞死亡，伴随着抑制丙二醛（MDA）和线粒体脂质过氧化物，这是由DOX诱导。此外，乙氧喹显着防止DOX诱导的细胞死亡，而没有任何抑制代表细胞凋亡的半胱天冬酶裂解。在DIC小鼠中，乙氧喹治疗改善了心脏损伤，如收缩功能障碍和心肌萎缩，以及肺充血。乙氧基喹还抑制血清乳酸脱氢酶和肌酸激酶活性，降低脂质过氧化物如MDA和丙烯醛的水平，抑制心脏纤维化，并减少DIC小鼠心脏中的TUNEL阳性细胞。因此，乙氧喹是一种有效的抗氧化剂，可预防DIC中的铁凋亡，并有望成为其治疗药物。
Abstract Doxorubicin (DOX) is an effective anti-cancer agent for various malignancies. Nevertheless, it has a side effect of cardiotoxicity, referred to as doxorubicin-induced cardiomyopathy (DIC), that is associated with a poorer prognosis. This cardiotoxicity limits the clinical use of DOX as a therapeutic agent for malignancies. Recently, ferroptosis, a form of regulated cell death induced by the accumulation of lipid peroxides, has been recognized as a major pathophysiology of DIC. Ethoxyquin is a lipophilic antioxidant widely used for food preservation and thus may be a potential therapeutic drug for preventing DIC. However, the efficacy of ethoxyquin against ferroptosis and DIC remains to be fully elucidated. Here, we investigated the inhibitory action of ethoxyquin against GPx4-deficient ferroptosis and its therapeutic efficacy against DOX-induced cell death in cultured cardiomyocytes and cardiotoxicity in a murine model of DIC. In cultured cardiomyocytes, ethoxyquin treatment effectively prevented GPx4-deficient ferroptosis. Ethoxyquin also prevented DOX-induced cell death, accompanied by the suppression of malondialdehyde (MDA) and mitochondrial lipid peroxides, which were induced by DOX. Furthermore, ethoxyquin significantly prevented DOX-induced cell death without any suppression of caspase cleavages representing apoptosis. In DIC mice, ethoxyquin treatment ameliorated cardiac impairments, such as contractile dysfunction and myocardial atrophy, and lung congestion. Ethoxyquin also suppressed serum lactate dehydrogenase and creatine kinase activities, decreased the levels of lipid peroxides such as MDA and acrolein, inhibited cardiac fibrosis, and reduced TUNEL-positive cells in the hearts of DIC mice. Collectively, ethoxyquin is a competent antioxidant for preventing ferroptosis in DIC and can be its prospective therapeutic drug.